Condensation of α-Amino Acid with Amine in the Absence of a Coupling Agent

Article abstract of DOI:10.1246/cl.2003.830

Treatment of N-(4-nitrophenoxycarbonyl)amino acid with an equimolar amount of amine in the absence of a coupling agent gave the corresponding α-amino acid amide in high yield.

Full text of DOI:10.1246/cl.2003.830

830
Chemistry Letters Vol.32, No.9 (2003)
Condensation of ꢀ-Amino Acid with Amine in the Absence of a Coupling Agent
Jun-ichi Yamaguchi,ꢀ Shinya Nagai, Emi Fukuoka, and Takayuki Suyamaꢀ
Department of Applied Chemistry, Faculty of Engineering, Kanagawa Institute of Technology,
Shimo-Ogino, Atsugi, Kanagawa 243-0292
(Received June 12, 2003; CL-030536)
Treatment of N-(4-nitrophenoxycarbonyl)amino acid with
an equimolar amount of amine in the absence of a coupling
agent gave the corresponding ꢀ-amino acid amide in high yield.
O
O
O
O
Et3N, THF
+
N
N
HO
NpO
O
NpO
Cl
0°C, 30 min
O
O
quant.
NpOCO2Su
NpOCOCl
HO-Su
4-Nitrophenyl N-substituted carbamate is known as a pre-
cursor of isocyanate1 and is utilized in the synthesis of multi-
substituted urea.2 On the other hand, isocyanate reacts with
some nucleophiles such as carboxamide3 and carboxylic acid4
to afford N-acylurea or carboxamide, respectively. From the
above reports, we assumed that treatment of N-(4-nitrophen-
oxycarbonyl)amino acid (Npoc-AA-OH) with amine generated
2-isocyanatocarboxylic acid, which, in turn, gave the corre-
sponding N-carboxy anhydride (NCA) by its intramolecular
cyclization. Since reaction of NCA with amine is reported,5
the corresponding ꢀ-amino acid amide will be obtained as a fi-
nal product. In this communication, we wish to report that treat-
ment of Npoc-AA-OH with amine gave the corresponding tert-
butoxycarbonyl(Boc)-AA-NHR2 in high to excellent yield after
tert-butoxycarbonylation by the use of Boc2O (Scheme 1).
From the above reaction system, Npoc-AA-OH can be regarded
as an acid component bearing a coupling agent. Generally, a
certain coulping agent is used such as some carbodiimides,6
uroniums,7 and phosphoniums8 in amide formation. On the con-
trary, the condensation of Npoc-AA-OH with amine proceeds
without a coupling agent, and this reaction system will be
new methodology for amide formation of ꢀ-amino acids.
R1
O
R1
NpOCO2Su, THF
OH
OH
H2N
O
NpO
N
50 °C, several hours
H
O
up to 70%
Npoc-AA-OH
H-AA-OH
Scheme 2. Preparation of Npoc-AA-OH.
Table 1. Solvent effect on amino acid amide formation using
Npoc-Phe-OH
Run
Solvent
Time/h
Yield/%
1
2
3
4
DMF
THF
MeOH
CH2Cl2
1
85
84
63
20
24
20
Not Detected
changed from colorless into yellow except that dichloromethane
was used as solvent. It was found that Boc-Phe-NH(CH2)2Ph
was obtained in high yield after tert-butoxycarbonylation using
Boc2O and the best result was given when DMF was used as
solvent (Table 1, Run 1).
As shown in Table 2, several Npoc-AA-OHs were convert-
1) H2NR2, DMF,
rt, 1 h
O
R1
R1
OH
Boc
NHR2
Table 2. Amino acid amide formation using Npoc-AA-OH
R3
NpO
N
N
H
H
2) Boc2O, 1.5 h
O
O
Run
AA
Yield/%
Boc-AA-NHR2
Npoc-AA-OH
1
2
3
4
5
6
7
8
9
10
11
12d
13d
14d
Leu
Val
Ile
Ala
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
CH2CO2Et
CH2CO2Et
CH2CO2Et
98
88
80
Boc = tert-butoxycarbonyl
Scheme 1. Amide formation using Npoc-AA-OH.
67 (79)a
46 (58b)a
78 (91)a
87
97
88
81
56 (76)
89
88
Because Npoc-AA-OH was obtained only in slight yield
when 4-nitrophenyl chloroformate, which was commonly pur-
chased, was used as 4-nitrophenoxycarbonyl agent under Shot-
ten–Baumann’s conditions, a new method for preparation of the
starting materials was examined. After several attempts, it was
found that N-(4-nitrophenoxycarbonyloxy)succinimide (NpO-
CO2Su) was effective to increase the yields of Npoc-AA-OH
(Scheme 2).
Most of Npoc-AA-OHs were obtained as crystals and could
be purified by reprecipitation from ethyl acetate with hexane ex-
cept for Npoc-Ile-OH, which was obtained as a viscous oil and
was purified by chromatography on silica gel (CHCl3:MeOH =
9:1). All Npoc-AA-OHs are stable at room temperature for three
months and in a freezer at least for one year.
Gly
Asn(Trt)c
Ser(OBut)
Trp
Met
Glu(OCH2Ph)
Pro
Phe
Trp
Glu(OCH2Ph)
72
aThe number in parentheses indicates the yield of Boc-AA-
NH(CH2)2Ph when the reaction was performed in the pres-
ence of 1.0 equimolar of DIEA. bReaction time; 3 h. Trt
c
= trityl. dThe reaction was performed in the presence of
1.0 equimolar amount of triethylamine.
When Npoc-Phe-OH was treated with phenethylamine in
some solvents at room temperature, all of the reaction mixture
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.9 (2003)
831
ed to the ꢀ-amino acid amide on treating with phenethyl-
amine.9 In most cases, Boc-AA-NH(CH2)2Ph was obtained in
high yield. However, the yields of Boc-AA-NH(CH2)2Ph were
low in the reactions using some Npoc-AA-OHs (Runs 4–6). In
these cases, an addition of diisopropylethylamine (DIEA) was
effective to improve the yield of Boc-AA-NH(CH2)2Ph. Bender
and Hormer reported that 4-nitrophenyl N,N-disubstituted car-
bamate is hydrolyzed about 106 times as slow as 4-nitrophenyl
N-substituted carbamate1 and hence it was suspected that no re-
action using Npoc-Pro-OH procceded. Boc-Pro-NH-(CH2)2Ph
was, nevertheless, obtained in 56% yield and its yield was in-
creased by addition of DIEA (Run 11). Reactions using H-
Gly-OEt hydrogen chloride as the amino component in the pres-
ence of an equimolar amount of triethylamine were examined.
In these cases, the corresponding dipeptides were also given
in high yields (Runs 12–14). In the present reaction system, it
might form by-product such as urea derivative (R2NHCO-
AA-OH) and/or dipeptide (Boc-AA-AA-NHR2). However,
since these by-products were not isolated, little amount of these
by-products would be produced.
In conclusion, we have developed a condensation reaction
of Npoc-AA-OH with amine in the absence of a coupling agent
to form the amino acid amide without racemization.
References and Notes
1
H. L. Bender and R. B. Homer, J. Org. Chem., 30, 3975
(1965); F. M. Menger and L. E. Glass, J. Org. Chem., 39,
2469 (1974).
2
N. Choy, K. Y. Moon, C. Park, Y. C. Son, W. H. Jung, H.-I.
Choy, C. S. Lee, C. R. Kim, and H. Yoon, Org. Prep.
Proced. Int., 28, 173 (1996); B. Raji, J. M. Kassir, and T.
P. Kogan, Bioorg. Med. Chem. Lett., 8, 3043 (1998); Q.
Liu, N. W. Luedtke, and Y. Tor, Tetrahedron Lett., 42,
1445 (2001).
3
4
M. Busch, G. Blume, and E. Pungs, J. Prakt. Chem./Chem.-
Zrg., 79, 513 (1909).
W. R. Sorenson, J. Org. Chem., 24, 978 (1959); I. S.
Blagbrough, N. E. Mackenzie, C. Ortiz, and I. Scott, Tetra-
hedron Lett., 27, 1251 (1986); A. C. Schuemacher and R.
W. Hoffmann, Synthesis, 2001, 243.
In the amide formation of ꢀ-amino acid, it is most impor-
tant that the ꢀ-amino acid amide is obtained without racemiza-
tion, so that a racemization check was made by HPLC. Peaks
corresponding to H-Phe-NH(CH2)2Ph prepared from (S)-
Npoc-Phe-OH were identified by comparison with rac-H-Phe-
NH(CH2)2Ph standard run under identical conditions. Since
(S)-H-Phe-NH(CH2)2Ph was detected in over 98% yield, the
present reaction proceeded without racemization.10
The proposed reaction mechanism is outlined in Scheme 3.
As pointed out before, 2-isocyanatocarboxylic acid, which is
generated by Npoc-AA-OH on treatment with amine, cyclizes
to give the corresponding NCA (Path A). Amine, in turn, attacks
NCA to give Boc-AA-NHR2 after evolution of carbondioxide
and tert-butoxycarbonylation. However, the reaction using
Npoc-AA-OH derived from imino acid, namely, proline, also
proceeded, so that we should also assume an addition–elimina-
tion process (Path B).
5
6
J. L. Bailey, J. Chem. Soc., 1950, 3461; Y. Knobler, S.
Bittner, and M. Frankel, J. Chem. Soc., 1964, 3941; Y.
Knobler, S. Bittner, D. Virov, and M. Frankel, J. Chem.
Soc. C, 1969, 1821.
Dicyclohexylcarbodiimide (DCC); J. C. Sheehan, P.
Cruickshank, and G. L. Boshart, J. Org. Chem., 26, 2525
(1961); 1-Ethyl-3-(30-dimethylaminopropyl)carbodiimide
hydrochloride (WSCꢁHCl); J. C. Sheehan, J. Preson, and
P. A. Cruickshank, J. Am. Chem. Soc., 87, 2492 (1965).
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumu
hexafluorophosphate (HBTU); R. Knorr, Tetrahedron Lett.,
30, 1927 (1989); M. S. Bernatowicz, Tetrahedron Lett., 30,
4645 (1989).
7
8
9
(Bezotriazole-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP); B. Castro, Tetrahedron Lett.,
1975, 1219.
General procedure for preparation of Boc-amino acid
amide: To a DMF solution (2.0 mL) of Npoc-amino acid
(0.2 mmol) was added 0.2 mmol of phenethylamine at room
temperature. After stirring for 1 h, 0.22 mmol of Boc2O was
added to the resulted yellow solution for 1.5 h. DMF was re-
moved under reduced pressure, organic materials were ex-
tracted with EtOAc. The organic layer was washed with
5% K2CO3 solution and brine, and the extract was dried
over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by preparative TLC
R1
H2NR2
O
HN
O
Path A
-NpOH
O
Npoc-AA-OH
H2NR2
-NpOH
O
N
Path B
O
AA=Pro
NpO
OH
(CHCl3:MeOH
NH(CH2)2Ph.
= 95:5 or 9:1) to give Boc-AA-
O
R1
R1
-CO2
NHR2
O
Boc
NHR2
HO
N
N
10 Conditions; column, Sumichiral OA-4700 (Sumika Chemi-
cal Analysis Service, Ltd.) 1.0 mL/min of 98 to 90% hexane
(EtOH containing 0.1% TFA) in 45 min; detection, 254 nm,
retention time, (S)-form, 21.5 min; (R)-form, 22.7 min.
Boc2O
H
H
O
Boc-AA-NHR2
Scheme 3. Proposed reaction pathways.
Published on the web (Advance View) August 11, 2003; DOI 10.1246/cl.2003.830